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Aconitase 2 inhibits the proliferation of MCF-7 cells promoting mitochondrial oxidative metabolism and ROS/FoxO1-mediated autophagic response.
- Source :
-
British Journal of Cancer . Jan2020, Vol. 122 Issue 2, p182-193. 12p. 5 Graphs. - Publication Year :
- 2020
-
Abstract
- <bold>Background: </bold>Deregulation of the tricarboxylic acid cycle (TCA) due to mutations in specific enzymes or defective aerobic metabolism is associated with tumour growth. Aconitase 2 (ACO2) participates in the TCA cycle by converting citrate to isocitrate, but no evident demonstrations of its involvement in cancer metabolism have been provided so far.<bold>Methods: </bold>Biochemical assays coupled with molecular biology, in silico, and cellular tools were applied to circumstantiate the impact of ACO2 in the breast cancer cell line MCF-7 metabolism. Fluorescence lifetime imaging microscopy (FLIM) of NADH was used to corroborate the changes in bioenergetics.<bold>Results: </bold>We showed that ACO2 levels are decreased in breast cancer cell lines and human tumour biopsies. We generated ACO2- overexpressing MCF-7 cells and employed comparative analyses to identify metabolic adaptations. We found that increased ACO2 expression impairs cell proliferation and commits cells to redirect pyruvate to mitochondria, which weakens Warburg-like bioenergetic features. We also demonstrated that the enhancement of oxidative metabolism was supported by mitochondrial biogenesis and FoxO1-mediated autophagy/mitophagy that sustains the increased ROS burst.<bold>Conclusions: </bold>This work identifies ACO2 as a relevant gene in cancer metabolic rewiring of MCF-7 cells, promoting a different utilisation of pyruvate and revealing the potential metabolic vulnerability of ACO2-associated malignancies. [ABSTRACT FROM AUTHOR]
- Subjects :
- *RESEARCH
*GENETIC mutation
*AUTOPHAGY
*RESEARCH methodology
*CELL physiology
*EVALUATION research
*MEDICAL cooperation
*OXIDATIVE stress
*HYDROLASES
*MITOCHONDRIA
*COMPARATIVE studies
*RESEARCH funding
*REACTIVE oxygen species
*CELL lines
*BREAST tumors
*ENZYME inhibitors
*PHARMACODYNAMICS
*CHEMICAL inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 00070920
- Volume :
- 122
- Issue :
- 2
- Database :
- Academic Search Index
- Journal :
- British Journal of Cancer
- Publication Type :
- Academic Journal
- Accession number :
- 141317500
- Full Text :
- https://doi.org/10.1038/s41416-019-0641-0